3-substituted-7-hydroxy lower alkyl benzodiazepines

ABSTRACT

The present invention relates to 7-hydroxy lower alkyl-3substituted benzodiazepines, compounds of biological interest as muscle relaxants, sedatives and anti-convulsants.

United St tes Patent [191 Ning et al.

[ 51 *Nov. 5, 1974 3-SUBSTITUTED-7-HYDROXY LOWER ALKYL BENZODIAZEPINESInventors: Robert Ye-Fong Ning, West Caldwell; Leo Henryk Sternbach,Upper Montclair, both of NJ.

Hoffmann-La Roche Inc., Nutley, NJ.

Assignee:

Notice: The portion of the term of this patent subsequent to Aug. 8,1989, has been disclaimed.

Filed: Dec. 10, 1971 Appl. No.: 206,932

US. Cl. 260/2393 D, 424/244 Int. Cl C07d 53/06 Field of Search 260/2393D References Cited UNITED STATES PATENTS 3/l965 Bell 260/2383 D Reederet al. 260/2393 D Ye-Fong Ning et al. 260/2393 D FOREIGN PATENTS ORAPPLICATIONS 1,447,040 6/1966 France 260/2393 D Primary ExaminerNorma S.Milestone Assistant ExaminerRobert T. Bond Attorney, Agent, orFirmSamuel L. Welt; Bernard S. Leon; William G. lsgro 15 Claims, NoDrawings 3-SUBS'IlITUTED-7-HYDROXY LOWER ALKYL BENZODIAZEPINES DETAILEDDESCRIPTION OF THE INVENTION The present invention relates to 7-hydroxylower alkyl -3substituted benzodiazepines of the formula wherein R R Rand R are each selected from the group consisting of hydrogen and loweralkyl, R is selected from the group consisting of hydrogen and halogenand R is selected from the group consisting of lower alkanoyloxy andhydroxy.

The term lower alkyl as utilized herein, unless otherwise specified,connotes both straight and branched chain C -C preferably C -Chydrocarbon groups, such as methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl and the like. By the term halogen" as utilized herein,there is contemplated all four forms thereof, i.e. chlorine, bromine,fluorine, and iodine, unless otherwise specified. The term loweralkanoyl" connotes the acyl moiety of a C -C lower alkanoic acid such asacetyl, propionyl, butyryl and the like.

Most preferred are compounds wherein a double bond is contained betweenpositions 4 and 5, i.e. compounds of the formula I above and R ishydroxy.

When R is halogen, most preferred are the halogens, chlorine orfluorine, most preferentially, fluorine. Also, when R, is other thanhydrogen, it is preferably joined to the S-phenyl ring at the 2-positionthereof. R, and R are preferably hydrogen. Also, in formula I or la, themost preferred member of the lower alkyl grouping is methyl.

Thus, as is evident from the above, in formula I or Ia,.

R R and R are all preferentially hydrogen or methyl, R is preferentiallyhydrogen and R is preferentially hydrogen or fluorine and, whenfluorine, is joined to the S-phenyl ring at the 2-position thereof. Mostpreferred is a compound of the formula I or la above wherein R ishydrogen, R is methyl, R is hydrogen or methyl, R is hydrogen and R isfluorine and R is hydroxy.

Compounds of the formula I or Ia above can be pre- 2 pared starting withthe corresponding compound of the formula ii NO R4 r Ri-C- u bn Ewherein R R R R and R are as above.

the preparation of compounds of the formula 11 above is disclosed inNing and Sternbach co-pending patent application Ser. No. 101,184, filedDec. 23, 1970.

More particularly, the compounds of the formula I in the first stage canbe prepared from the corresponding compounds of the fonnula II by firstoxidizing the compound of the formula II with any suitable oxidizingagent such as hydrogen peroxide or peracids. Such compounds obtainedthusly are of the formula wherein R R R R and R are as above.

Compounds of the formula III in addition to being useful in and ofthemselves for pharmacological purposes are also useful as intermediatesin the preparation of compounds of the formula I and la above.

Representative of peracids suitable for the oxidation step includeperacetic acid, trifluoroperacetic acid, mchloroperbenzoic acid,perphthalic acid, persulfuric acid and the like.

The desired oxidation can be accomplished in a variety of ways. In oneembodiment, a compoundof the formula II is added to an acidic medium,followed by the addition of the peracid thereto.

Alternatively, the peracid can be prepared in situ and the compound ofthe formula II which is to be oxidized can then be added to theresultant mixture whereby a compound of the formula 111 results. Theperacid is prepared by mixing hydrogen peroxide with a straight chainalkanoic acid or a functional derivative thereof, for example, aceticacid, m-chlorobenzoic acid and the like.

Temperature is not a critical feature of the oxidation step in eitheralternative approach, but it is preferred to effect the oxidation atroom temperature or slightly above or slightly below room temperature.

The so-obtained compounds of the formula III can then be rearranged tothe compounds of the formula 1 wherein R is lower alkanoyloxy by gentlywarming a compound of the formula III in the presence of an acylatingagent capable of providing the acyl moiety of a C -C lower alkanoicacid. Preferred acylating agents include acid anhydrides, diacylsulfides or an acid halide (preferably an acid chloride). If R isacetoxy, pre ferred among the many acylating agents are aceticanhydride, diacetyl sulfide or acetyl chloride. Among the many othersuitable acylating agents, there can be included propionic acidanhydride, butyric acid anhydride, butyryl chloride, propionyl chloride,dipropionyl sulfide and the like.

The conversion of a compound of the formula III above to the compound ofthe formula I above wherein R is lower alkanoyloxy can be effected inthe presence of any suitable inert organic solvent such asdimethylformamide, tetrahydrofuran, methylene chloride and the like.Alternatively, the acylating agent utilized can itself serve as thereaction medium. In a preferred embodiment, the acylating agent, e.g.acetic anhydride, is utilized as the reaction medium. Thus, by thissimple step, there is provided to the reaction zone, the medium in whichthe reaction can be effected as well as the necessary reaction partner.

The 3-hydroxy compounds of the formula I wherein R is hydroxy can beobtained from the corresponding compounds of the formula I or Ia abovewherein R is lower alkanoyloxy by gently warming the latter in thepresence of an aqueous solution of acid or base. Among the many baseswhich may be present in the reaction zone to effect the desiredhydrolysis, there can be included sodium hydroxide, potassium hydroxideand the like. The removal of the acyl group preferably occurs atslightly elevated temperatures, although temperature is not critical.

Compounds of the formula I wherein R is lower alkanoyloxy can also beconverted into the corresponding compounds of the formula I wherein R ishydroxy by acid hydrolysis.

Said acid hydrolysis can be advantageously effected by treating thecompound of the formula I wherein R is lower alkanoyloxy with an aqueoussolution of a mineral acid such as hydrochloric acid, hydrobromic acid,sulfuric acid and the like or an organic acid such as toluenesulfonicacid or the like. The hydrolysis with acid is also suitably effected bygentle warming, but such is not critical and the hydrolysis can beconducted at room temperature or higher or lower temperatures.

Said acid or basic hydrolysis can suitably be effected in an aqueousmedium containing an organic solvent such as dioxane, tetrahydrofuran orlike organic solvents. All that is required of the organic solvent isthat it be miscible with water.

Similarly, compounds Ia wherein R is lower alkanoyloxy can be convertedinto corresponding compounds of the formula Ia wherein R is hydroxy.

Compounds of the formula I above wherein R, is hydrogen can also beprepared from the corresponding compounds of the formula dride.Representative of metal borohydride useable for this purpose include,preferentially, alkali metal borohydrides such as sodium borohydride.Magnesium borohydride can also be efficaciously utilized. By the use ofa mild reductant such as a metal borohydride, the reduction of thecarbonyl group in position-7 of the compound of the formula IV occurswithout substantially effecting the other reduceable moieties present inthe molecule under the reaction conditions employed.

The reduction with metal borohydrides preferably proceeds in an inertorganic solvent. Among the many inert organic solvents that may beadvantageously utilized, there can be included lower alkanols such asmethanol, ethanol, propanol and the like, ethers such as tetrahydrofuranand the like, dimethylsulfoxide, dimethylformamide and/or any othersuitable inert organic solvent. Preferably, the reduction is effected ata temperature from about 20 to about In the most preferred processaspect, this reduction is effected at about a temperature range of fromabout 0C. to about 25C., most preferably at about room temperature.

In an alternate process aspect, compounds of the formula IV abovewherein R is hydrogen and R is hydroxy can be treated with a lower alkyllithium (R Li) in the manner described more fully hereinafter to obtaina corresponding compound of the formula I wherein R is lower alkyl and Ris hydroxy. The most advantageous of the lower alkyllithiums for thepurposes of the present invention is methyl lithium. However, otherlower alkyl lithiums can also be utilized such as ethyl lithium, propyllithium, butyl lithium, pentyl lithium, and the like.

In a preferred embodiment, the reaction utilizing a lower alkyl lithiumis carried out in the presence of an inert solvent. It will beappreciated that the use of such type solvent will ordinarily allow thereaction to proceed in a relatively simple manner, thereby avoiding theuse of extraordinary conditions, extensive equipment and the like. Inertsolvents capable of functioning efficaciously in this process stepinclude benzene, tetrahydrofuran, dioxane and the like or any otherappropriate inert solvent. Suitably, the reaction proceeds attemperatures much below room temperature. A preferred reactiontemperature range is from about 1 00 to about 0, most preferably between80 to 50.

The compounds of the formula I above, wherein R is hydroxy can beprepared directly from the compound of the formula IV above wherein R islower alkanoyloxy by having'present in the reaction zone in addition toa reducing agent of the type described above, a substance which iscapable of hydrolyzing the acyl moiety of the lower alkanoyloxy group atR Conveniently, a reaction medium containing tetrahydrofuran andmethanol, a metal borohydride, such as sodium borohydride and a basesuch as sodium hydroxide can be efficaciously utilized. In this manner,the reduction of the 7-acyl substituent to the corresponding 7- hydroxylower alkyl grouping and hydrolysis to the 3- hydroxy group occursconcurrently. It has been observed that when proceeding accordingly,there may be obtained amixture of a compound of the formula I abovewherein R is lower alkanoyloxy and a compound of the formula I abovewherein R is hydroxy.

It is, of course, to be understood that a compound of the formula IVwherein R is lower alkanoyloxy can be reduced to the correspondingcompound of the formula I wherein R is lower alkanoyloxy and theresultant compound can be deacylated in the manner described above tothe corresponding compound of the formula I wherein R is hydroxy. As isevident from the above, the hydroxy compound can also be convenientlyobtained in a single step from a compound of the formula IV wherein R islower alkanoyloxy.

The compound of the formula IV can be prepared starting with the knowncompound of the formula wherein R R R and R are as above by firstoxidizing a compound of the formula V above in the same manner asdescribed above in connection with the conversion of a compound of theformula II above into the corresponding compound of the formula III.

By oxidizing a compound of the formula V accordingly, there is obtaineda compound of the formula Rs i l-'0' wherein R R R and R are as above.

The so-obtained product of the formula VI is then rearranged to thecorresponding compound of the formula IV wherein R is lower alkanoyloxyin the same manner as described above in connection with the conversionof a compound of the formula III into the corresponding compound of theformula I wherein R is lower alkanoyloxy.

If desired, the compound of the formula IV wherein R is loweralkanoyloxy can be deacylated to the corresponding compound of theformula IV wherein R is hydroxy in the same manner as described above inconnection with the conversion of a compound of the formula I wherein Ris lower alkanoyloxy to the corresponding compound of the formula Iwherein R is bydroxy.

Compounds of the formula I and la above wherein R is hydrogen and R ishydroxy and compounds of the formula III above wherein R is hydrogen canbe converted into the corresponding compounds of the formula I and IIIrespectively wherein R is lower alkyl by first forming the sodioderivative of a compound of the formula I, la or III above with analkali metal alkoxide, e.g., sodium methoxide, potassium t-butoxide andthe like oran alkali metal hydride, such as sodium hydride and the likeand treating the so-obtained said sodio derivative with an alkylatingagent such as a lower alkyl halide, e.g., methyl iodide or ethyl iodide,a dilower alkyl sulfate, such as dimethylsulfate and the like wherebyalkylation of the nitrogen atom in the 1- position of the benzodiazepineresults.

Compounds of the formula I canbe egnverted into the correspondingcompounds of the formula Ia above by reducing the former by anyconveniently available technique. For example, the reduction of acompound of the formula I above to a compound of the formula Ia abovecan be effected catalytically by hydrogenation in the presence of aplatinum catalyst. Also, the reduction can be effected utilizing Raneynickel. Conveniently, the reduction is effected in the presence of anysuitable inert organic solvent. Among the many solvents there can beincluded lower alkanols such as methanol, ethanol and the like, etherssuch as diethyl ether and tetrahydrofuran and similar solvents.Temperature is not critical to a successful performance of the reductionstep and so the reduction can be conducted at room temperature or aboveor below room temperature.

As is indicated above, the compounds of the formula I, la and Ill aboveare useful as anti-convulsants, muscle relaxants and sedatives. Suchcompounds can be formulated into pharmaceutical preparations inadmixture with a compatible pharmaceutical carrier and can beadministered enterally or parenterally with dosages suited to fit theexirgencies of a pharmacological situation. As contemplated by thisinvention, the novel compounds of the formula I, la and Ill can beembodied in a pharmaceutical dosage formulation containing from about0.5 mg. to about 200 mg. of active substance with dosage adjusted tospecies and individual requirements (parenteral formulations wouldordinarily contain less of the active substance than compositionsintended for oral administration). The novel compounds of this inventioncan be administered alone or in combination with pharmaceuticallyacceptable carriers as indicated above in a wide variety of dosageforms. Suitably, the dosage regimen consists of four tablets of 50 mg.each given daily.

In addition to compounds of the formula I, la and III above, there isalso encompassed with the invention, the pharmaceutically acceptablesalts of said compounds and the compounds of the formula I, la and IIIabove can be administered in the form of such salts. The compounds ofthe formula I, la and III above form acid addition salts withpharmaceutically acceptable acids, for example, with organic orinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, phosphoric acid, nitric acid, citric acid, tartaric acid,

salicylic acid, ascorbic acid, maleic acid, formic acid and the like.

Solid preparations of compounds of the formula I, la and III above orsalts thereof for oral administration can include tablets, capsules,powders, granules, emulsions, suspensions and the like. The solidpreparations may comprise an inorganic carrier, e.g., talc, or anorganic carrier, e.g., lactose, starch. Additives such as magnesiumstearate (a lubricant) can also be included. Liquid preparationscontaining a compound of the formula I, la and III above or saltsthereof such as solutions, suspensions or emulsions may comprise theusual diluents such as water, petroleum jelly and thelike, a suspensionmedia such as polyoxyethylene glycols, vegetable oils and the like. Theymay also contain other additional ingredients such as preserving agents,stabilizing agents, wetting agents, salts for varying the osmoticpressure or buffers. They may also contain, in combination, othertherapeutically useful substances.

The following examples are illustrative but not limitative of thepresent invention. All temperatures are stated in degrees Centigrade.

EXAMPLE 1 A suspension of 5.60 g (20.0 mmol) of l,3-dihydro- 7-(1-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin- 2-one in 50 ml of aceticacid was heated to give a clear solution. In this solution at roomtemperature, was dissolved 5.20 g (30.0 mmol) of m-chloroperbenzoicacid. The mixture was allowed to stand at room temperature overnight.

Acetic acid was evaporated in vacuo. The residue was partitioned betweenaqueous sodium bicarbonate and methylene chloride. The methylenechloride layer was dried over anhydrous sodium sulfate, then evaporatedto dryness. The residue on crystallization from acetone-hexane yieldedl,3-dihydro-7-( lhydroxyethyl)--phenyl-2H-1,4-benzodiazepin-2-one4-oxide as colorless prisms, m.p. l88l90.

EXAMPLE 2 A suspension of 6.00 g. (20.0 mmol) of l,3-dihydro- 5-(2-fluorophenyl)-7-( l-hydroxyethyl)-2H-1,4- benzodiazepin-Z-one in 50 mlacetic acid was heated to give a clear solution. In this solution, atroom temperature was dissolved 5.20 g (30.0 mmol) of mchloroperbenzoicacid. The solution was allowed to stand at room temperature overnight.

The acetic acid was removed in vacuo. The residue was partitionedbetween aqueous sodium bicarbonate and methylene chloride. The methylenechloride layer was dried over anhydrous sodium sulfate then evaporatedto dryness. The residual gum crystallized from ether to give1,3-dihydro-5-(2-fluorophenyl)-7-(lhydroxyethyl)-2H-l,4-benzodiazepin-2-one4-oxide as light yellow amorphous solid. The melting point was in therange of l25-l40.

EXAMPLE 3 To a solution of 0.5 g (1.48 mmol) of 3-acetoxy-7- acetyl- 1,3-dihydro-5-phenyl-2l-I- l ,4-benzodiazepin- Zone in 50 ml. of a 1:1mixture of tetrahydrofuran and ethanol was added 83 mg (2.2 mmol) ofsodium borohydride in one portion. The solution was left standing atroom temperaturefor 2 hrs. A few drops of acetic acid were added untilno more hydrogen evolved and the mixture was evaporated to dryness. Theresidue was dissolved in tetrahydrofuran and passed through a pad ofsilica gel (about 15 g) which was further eluted with ethyl acetatecontaining of methanol. Evaporation of solvents gave a gum which wasdissolved in tetrahydrofuran and separated by thick layer chromatographyon eight 20 cm X 20 cm X 2mm silica gel plates, developed in ethylacetate. The band corresponding to 3- acetoxy-l ,3-dihydro-7-(l-hydroxyethyl)-5-phenyl-2H- 1,4-hcnzodiazepin-2-one (Rf 0.52) wasscraped together, eluted from silica gel with 10% methanol-ethyl acetateand evaporated to a gum. The gum was crystallized from acetone-hexane togive colorless needles of 3-acetoxy-l ,3-dihydro-7-(l-hydroxyethyl)-5-phenyl- 21-1-1,4-benzodiazepin-2-one, m.p. 233235.

The band corresponding to the hydroxy compound l,3-dihydro-3-hydroxy-7-(1-hydroxyethyl)-5-phenyl- 2H-l,4-benzodiazepin -2-one was collected thesame way and evaporated to a gum which was crystallized fromacetone-hexane to give l,3-dihydro-3-hydroxy-7-(1-hydroxyethyl)-5-phenyl-2l-ll ,4-benzodiazepin- 2-one of m.p. 172-1743-Acetoxy-7-acetyll ,3-dihydro-5-phenyl-2H-l ,4- be'nzodiazepin-Z-oneutilized as a starting material was 100 ml ofmethylene chloride wasadded 6 g (30 mmol) of m-chloroperbenzoic acid. The reaction was stirreduntil a complete solution was obtained and then left at room temperaturefor 24 hr. The solution was concentrated to a small volume and 3.2 g ofmchlorobenzoic acid was separated by filtration. The filtrate wasdiluted slowly with ether and the crude crystalline reaction productmelting at l93l95, was separated by filtration. After recrystallizationfrom acetone, 7-acetyl-l ,3-dihydro-5-phenyl-2H-l ,4-benzodiazepin-Z-one 4-oxide formed yellow needles melting at 208209.

A mixture of 1.4 g of 7-acetyl-l,B-dihydro-S-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide and 25 ml of acetic anhydride washeated on the steambath for 25 min. The solution was concentrated todryness. Crystallization of the residue from a mixture of benzene andether gave crude product melting at 225227. After recrystallization froma mixture of methylene chloride and ether3-acetoxy-7-acetyl-l,3-dihydro-5-phenyl- 21-1-1,4-benzodiazepin-2-oneformed slightly yellow prisms melting at 237238.

EXAMPLE 4 l,3-Dihydro-7-( 1-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide mg, 3.38 mmol) was heated to dissolve in 3.0ml of acetic anhydride on a steam bath. The heating was continued for 15mins.

The mixture was chromatographed on two 20 cm X 20 cm X 2 mm silica gelplates using ethyl acetate as eluent. The bands corresponding tocompound 3- acetoxy-l ,3-dihydro-7-( 1-hydroxyethyl)-5-phenyl-2l-l- 1,4-berizodiazepin-Z-one were isolated and eluted from silica with ethylacetate containing 10% of methanol. Evaporation of solvents gave an oilwhich on crystallization from acetone-hexane gave 3-acetoxy-1,3-dihydro-7-(1-hydroxyethyl)-5-phenyl-2H-1,4- benzodiazepin-2-one ascolorless amorphous solid, mp. 229-232.

EXAMPLE 5 To a solution of 0.5 g (1.4 mmol) of 3-acetoxy-7- acetyl-l,3-dihydro-5-( 2-fluorophenyl)-2l-ll ,4- benzodiazepin-2-one in 80 ml ofa 1:1 mixture of tetrahydrofuran and ethanol was added 80 mg (2.1 mmol)of sodium borohydride in one portion. The mixture was stirred at roomtemperature for 2 hrs. A few drops of acetic acid were then added untilno more hydrogen evolved. The mixture was evaporated to dryness. Theresidue was partitioned between methylene chloride and water. Themethylene chloride layer was washed with water, dried over anhydroussodium sulfate and evaporated to dryness. The residue was dissolved inmethylene chloride and separated by thick layer chromatography on four20 cm X 20 cm X 2 mm silica gel plates developed in ethyl acetate. Theband corresponding to the acetoxy compound (Rf 0.55) was scrapedtogether, eluted from silica gel with ethyl acetate containing 10%methanol and evaporated to a gum. The gum was crystallized fromacetone-hexane to give colorless amorphous 3-acetoxy-l,3-dihydro-5-(2-fluorophenyl)-7-( l-hydroxyethyl)-2H-1,4- benzodiazepin-2-one, m.p.2l32l5.

The band corresponding to the hydroxy compound (Rf 0.4) was collected inthe same way and evaporated to a gum which was crystallized frommethylene chloride to give the desired product 1,3-dihydro--(2-fluorophenyl)-3-hydroxy-7-( 1-hydroxyethyl)-2H-l,4- benzodiazepin-2-one,m.p. l20-l40.

3-Acetoxy-7-acetyl-l ,3-dihydro-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one utilized above was prepared as follows:

To a stirred suspension of 29.6 g (0.1 mol) of 7- acetyll,3-dihydro-5-(2-fluorophenyl )-2H- 1 ,4- benzodiazepin-2-one in 600 mlof methylene chloride was added 25 g (0.12 mol) of 85%mchloroperoxybenzoic acid. The mixture was stirred for about mins. untila clear solution was obtained and then left standing at'room temperaturefor hr. The methylene chloride solution was washed with ice cold dilutesodium bicarbonate, separated, dried and concentrated to dryness. Theresidue was crystallized from acetone and gave crude product melting at2l0-2l2 dec. After recrystallization from the same solvent, 7- acetyl-l,3-dihydro-5-( 2-fluorophenyl)-2H-l ,4- benzodiazepin-2-one 4-oxideformed colorless plates A suspension of 6.2 g. (20 mmol) of7-acetyl-1,3-

- dihydro-5-(2-fluorophenyl)-2l-l-1,4-benzodiazepin- EXAMPLE 6l,3-Dihydro-5-( 2-fluorophenyl )-7-( l-hydroxyethyl)-2H-l,4-benzodiazepin-2-one 4-oxide (100 mg, 3.38 mmol) was heated with3.0 ml of acetic anhydride on a steam bath for 15 mins.

The solution was chromatographed on two 20 cm X- 20 cm X 2 mm silica gelplates, using ethyl acetate as eluent. The bands corresponding tocompound 3- acetoxyl ,3-dihydro-5-(2-fluorophenyl)-7-( lhydroxyethyl)-2-H-1,4-benzodiazepin-2-one were isolated and eluted from silica gelwith ethyl acetate containing 10% of methanol. Evaporation of solventsgave an oil which on crystallization from acetone-hexane gave 3-acetoxyl,3-dihydro-5-(2-fluorophenyl)-7-(lhydroxyethyl)-2H-l,4-benzodiazepin-2-one as a colorless amorphoussolid, m.p. 205208.

EXAMPLE 7 A mixture of 1.18 g (4.0 mmol) of 7-acetyl-l,3-dihydro-3-hydroxy-5-phenyl-2H- l .4-benzodiazepin- 2-one, 0.228 g (6.0mmol) of sodium borohydride, 60 ml of ethanol and 60 ml oftetrahydrofuran was stirred at room temperature. In 20 mins. a clearsolution formed. After 2 hrs, the excess hydride was decom- 10 byrecrystallizations from acetone-hexane, m.p. l72-l74.

The 7-acetyl-3-hydroxyl ,3-dihydro-5-phenyl-2H- l,4-benzodiazepin-2-oneutilized as a starting material was prepared as follows:

To a stirred solution of 1.7 g of 3-acetoxy-7-acetyl-1,3-dihydro-5-phenyl-2H- l ,4-benzodiazepin-2-onc in 40 ml of dioxanewas added 10 ml of l N sodium hydroxide. The reaction mixture wasstirred at room temperature for 0.5 hr. A crystalline precipitate hadformed which dissolved after the addition of 10 ml of l N hydrochloricacid. The solution was concentrated to a small volume. Water was addedto the oily residue and the mixture was extracted with methylenechloride. The organic extract was dried and concentrated in vacuo todryness. Crystallization of the residue from acetone gave the productand after recrystallization from the same solvent gave7-acetyl-3-hyd'roxy-l,3- dihydro-5-phenyl-2l-l-l,4-benzodiazepin-2-oneas colorless needles melting point 2092l0.

EXAMPLE 8 A mixture of 1.252 g (4.0 mmol) of 7-acetyl-l,3-dihydro-5-(2-fluorophenyl)-3-hydroxy-2H-l ,4- benzodiazepin-Z-one, 0.228g (6.0 mmol) of sodium borohydride, 40 ml. of ethanol and 40 ml. oftetrahydrofuran was stirred at room temperature. In 15 mins.,

a clear solution formed. After 2 hrs., excess hydride was decomposed bythe addition of a few drops of acetic acid. Solvents were evaporated.The residue was stirred with a mixture of about 3 ml of water and 30 mlof tetrahydrofuran. Anhydrous sodium sulfate was added to retain theaqueous salt solution. The tetrahydrofuran solution was decanted. Thewet salty mass was washed three times by decantation withtetrahydrofuran. The combined tetrahydrofuran solution was filteredthrough a pad of silica gel, which was then washed with 100 ml of ethylacetate containing 10% of methanol. Evaporation of solvents yielded agum. The gum was dissolved in ml of boiling methylene chloride. The hotsolution was filtered to remove a trace of insoluble material. Onconcentration to about 20 ml followed by chilling, the solution yielded1,3-dihydro- 5-(2-fluorophenyl)-3-hydroxy-7-( l-hydroxyethyl)-2H-1,4-benzodiazepin-2-one as colorless needles, in the range of l25l40.

EXAMPLE 9 To a solution of 0.5 g (1.4 mmol) of 3-acetoxy-7-acetyl-l,3-dihydro-5-(2- fluorophenyl)-2l-l-l ,4- benzodiazepin-Z-one inml of a 1:1 mixture of tetrahydrofuran and ethanol was added 80 mg (2.1mmol) of sodium borohydride in one portion. Then 3 ml of l' N sodiumhydroxide was added and the mixture was stirred at room temperature for1.5 hrs. A few drops of acetic acid were added until no more hydrogenevolved. The mixture was evaporated to dryness. The residue waspartitioned between methylene chloride and water. The methylene chloridelayer was washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. 1,3-Dihydro-5-(2- fluorophenyl )-3-hydroxy-7-(l-hydroxyethyl)-2H-l ,4- benzodiazepin-Z-one in the residue wascrystallized from methylene chloride to give the desired product (m.p.l20-l40d)- EXAMPLE 10 benzodiazepin-2-one in 10 drops of tetrahydrofuranwas added 3 drops of l N sodium hydroxide. The mixture was left standingat room temperature for 0.5 hr. yieldingl,3-dihydro-5-(Z-fluorophcnyl)-3-hytlroxy-7- (l-hydroxyethyl)-2H- l,4-benzodiazepin-Z-one.

EXAMPLE ll A mixture of 3 g of 7-acetyl-5-(Z-fluorophenyl)-1,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one and 3 g of 85%m-chloroperbenzoic acid in 30 ml of methylene chloride was stirred about10 mins. until a solution formed. The solution was left standing at roomtemperature for 20 hrs. The reaction mixture was diluted with methylenechloride and washed with ice cold 1 N sodium hydroxide. The organiclayer was separated, dried and concentrated to dryness. The residuecrystallized from acetone and gave 7 -acetyl-5-(2-fluorophenyl)-l,3-dihydro-l-methyl-2H-l ,4-benzodiazepin-2-one 4- oxide melting at8586. After recrystallization from acetone, the melting point wasunchanged. The colorless prisms were found to have crystallized with 0.6mol acetone.

EXAMPLE 12 A suspension of 8 g of 7-acetyl-5-(2-fluorophenyl)-1,3-dihydrol -methyl-2H- l ,4-benzodiazepin-2-one 4- oxide in 30 ml ofacetic anhydride was heated on a steam bath for 1 hr. The reactionmixture was concentrated to dryness. The residue crystallized from amixture of ether and petroleum ether to give 3-acetoxy-7- acetyl-5-(2-fluorophenyl)- l ,3-dihydrol -methyl-2H- l,4-benzodiazepin-2-one,melting at l45147. After recrystallization from ether the product formedcolorless crystals with unchanged melting point.

EXAMPLE 13 EXAMPLE l4 7-Acetyl-5-(2-fluorophenyl)-3-hydroxy-1,3-dihydr0-l-methyl-ZH-l ,4-benzodiazepin-2-one so prepared was converted into5-(2-fluorophenyl)-3-hydroxy-7-(lhydroxyethyl)-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-Z-one by a procedure analogous to that described inExample 9.

EXAMPLE 15 A 25 mg. capsule containing the following:

mg[capsule l,3-Dihydro 3-hydroxy-7 l-hydroxycthyl) 25 -5-phenyl-2H-l4-benzodiazepin-2-one lactose 153 corn starch 30 magnesium stearate 2Total weight 2l0 mg.

can be prepared as follows:

Blend drug with lactose, and corn starch in a suitable mixer/Passblended mixture through a Fitzmill machine to obtain uniform mixture.Return powders to Blender, add talc and premix. Fill into empty hardshell capsule, No. 4 size on a capsule filling machine.

EXAMPLE 16 A 25 mg. tablet formulation containing the following:

mgztablet l,3-Dihydro-3-hydroxy-7-( l-hydroxyethyl) 25-5-phenyl-2H-1,4-benzodiazepin-2-one dicalcium phosphate, dihydrate,unmilled corn starch 30 microcrystalline cellulose 23 calcium stearate 2Total weight 230 R4 Nu wherein R R R and R are each selected fromthegroup consisting of hydrogen and lower alkyl, R is selected from thegroup consisting of hydrogen and halogen and R is selected from thegroup consisting of lower alkanoyloxy and hydroxy.

2. A compound as defined in claim 1 wherein R and R are hydrogen.

3. A compound as defined inclaim 2 wherein R is methyl, R is selectedfrom the group consisting of hydrogen and methyl and R is selected fromthe group consisting of hydrogen, chlorine and fluorine as is joined tothe phenyl ring in the 2-position thereof.

4. A compound as in claim 3 wherein R is hydroxy and R is hydrogen orfluorine.

5. A compound as defined in claim 4 of the formulal,3-dihydro-3-hydroxy-7-( l-hydroxyethyl)-5-phenyl- 2H-1,4-benzodiazepin-2-one.

6. A compound as defined in claim 4 of the formulal,3-dihydro-3'hydroxy-7-( l-hydroxyethyl )-5-( 2-fluorophenyl)-2H-1,4-benzodiazepin-2-one.

7. A compound as defined in claim 3 wherein R is acetoxy. I

8. A compound as defined in claim 7 of the formula3-acetoxy-1,3-dihydro-7-( l-hydroxyethyl)-5-phenyl- 2H-l,4-benzodiazepin-2-one.

9. A compound as defined in claim 7 of the formula3-acetoxy-1,3-dihydro-5-(2-fluorophenyl)-7-( lhydroxyethyl)-2H-l,4-benzodiazepin-2-one.

10. A compound of the formula 2 14. A compound as defined in claim 12 ofthe for- NC mula 1 ,3-dihydro-7-( l-hydroxyethyl)-5-phenyl-2H- R R41,4-benzodiazepin-2-one 4-oxide. (I: 15. A compound of the formula R2-\C N H 5 Rs OH l O R4 R R1 RZ- R0 OH C=N wherein R R R and R are eachselected from the group consisting of hydrogen and lower alkyl and R isselected from the group consisting of hydro- R5 gen and halogen. 11. Acompound as defined in claim wherein R and R are hydrogen.

12. A compound as defined in claim 11 wherein R is methyl, R is selectedfrom the group consisting of wherein R R R and R are each selected fromthe hydrogen and methyl and R is selected from the group groupconsisting of hydrogen and lower alkyl, R is consisting of hydrogen andfluorine. selected from the group consisting of hydrogen and 13. Acompound as defined in claim 12 of the forhalogen and R is selected fromthe group consistmula l,3-dihydro-7-( l-hydroxyethyl)-5-(2- ing of loweralkanoyloxy and hydroxy. fluorophenyl)-2l-l 1,4 hengodiazepin-2-one 4-ogide I i 9 UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO. U.S. Patent No. 3,846,410

DATED November 5, 1974 0 (5) Robert Ye-Fong Ning and Leo Hen rykSternbach It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

a Column 12, line 49 "as" should be and.

Column 14, line 10 C=N should be on NH Signed and Sealed thisTwenty-seventh Day Of July 1976 [SEAL] Arrest:

RUTH C. MASON c. MARSHALL DANN Arresting Officer Commissioner nflatenrsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A compound as defined in claim 1 whereinR1 and R4 are hydrogen.
 3. A compound as defined in claim 2 wherein R2is methyl, R3 is selected from the group consisting of hydrogen andmethyl and R5 is selected from the group consisting of hydrogen,chlorine and fluorine as is joined to the phenyl ring in the 2-positionthereof.
 4. A compound as in claim 3 wherein R6 is hydroxy and R5 ishydrogen or fluorine.
 5. A compound as defined in claim 4 of the formula1,3-dihydro-3-hydroxy-7-(1-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one.
 6. A compound as defined in claim 4 of the formula1,3-dihydro-3-hydroxy-7-(1-hydroxyethyl)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one.
 7. A compound as defined in claim 3 wherein R6 isacetoxy.
 8. A compound as defined in claim 7 of the formula 3-acetoxy-1,3-dihydro-7-(1-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one.
 9. Acompound as defined in claim 7 of the formula 3-acetoxy-1,3-dihydro-5-(2-fluorophenyl)-7-(1-hydroxyethyl)-2H-1,4-benzodiazepin-2-one.10. A compound of the formula
 11. A compound as defined in claim 10wherein R1 and R4 are hydrogen.
 12. A compound as defined in claim 11wherein R2 is methyl, R3 is selected from the group consisting ofhydrogen and methyl and R5 is selected from the group consisting ofhydrogen and fluorine.
 13. A compound as defined in claim 12 of theformula1,3-dihydro-7-(1-hydroxyethyl)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one4-oxide.
 14. A compound as defined in claim 12 of the formula1,3-dihydro-7-(1-hydroxyethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one4-oxide.
 15. A compound of the formula